title: Development of thiophenic analogues of benzothiadiazine dioxides as new powerful potentiators of 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors.
abstract: On the basis of the results obtained in previous series of AMPA potentiators belonging to 3,4-dihydro-2H-benzo- and 3,4-dihydro-2H-pyrido-1,2,4-thiadiazine 1,1-dioxides, the present work focuses on the design of original isosteric 3,4-dihydro-2H-thieno-1,2,4-thiadiazine 1,1-dioxides. Owing to the sulfur position, three series of compounds were developed and their activity as AMPA potentiators was characterized. In each of the developed series, potent compounds were discovered. After screening the selected active compounds on a safety in vivo test, 6-chloro-4-ethyl-3,4-dihydro-2H-thieno[2,3-e]-1,2,4-thiadiazine 1,1-dioxide (24) appeared as the most promising compound and was further evaluated. Its effects on long-term potentiation in vivo and on AMPA-mediated noradrenaline release were measured to predict its potential cognitive enhancing properties. Finally, an object recognition test performed in mice revealed that 24 was able to significantly enhance cognition, after oral administration, at doses as low as 0.3 mg/kg. This study validates the interest of the isosteric replacement of the benzene or pyridine nuclei by the thiophene nucleus in the ring-fused thiadiazine dioxides class of AMPA potentiators.
authors.affiliation: Centre Interfacultaire de Recherche du Médicament (CIRM)-Laboratoire de Chimie Pharmaceutique, University of Liege , Avenue de l'Hôpital 1, B36, 4000 Liège, Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Francotte
authors.forename: Eric
authors.initials: E
authors.lastname: Goffin
authors.forename: Pierre
authors.initials: P
authors.lastname: Fraikin
authors.forename: E
authors.initials: E
authors.lastname: Graindorge
authors.forename: Pierre
authors.initials: P
authors.lastname: Lestage
authors.forename: Laurence
authors.initials: L
authors.lastname: Danober
authors.forename: Sylvie
authors.initials: S
authors.lastname: Challal
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rogez
authors.forename: Olivier
authors.initials: O
authors.lastname: Nosjean
authors.forename: Daniel-Henri
authors.initials: DH
authors.lastname: Caignard
authors.forename: Bernard
authors.initials: B
authors.lastname: Pirotte
authors.forename: Pascal
authors.initials: P
authors.lastname: de Tullio
mesh_terms: D000818:Animals; D001581:Benzothiadiazines / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D003071:Cognition / Q000187:drug effects; D003499:Cyclic S-Oxides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003981:Diazoxide / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D018690:Excitatory Amino Acid Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D017774:Long-Term Potentiation / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008956:Models, Chemical; D015394:Molecular Structure; D009638:Norepinephrine / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D018091:Receptors, AMPA / Q000819:agonists* / Q000378:metabolism; D013829:Thiadiazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013876:Thiophenes / Q000737:chemistry; D014982:Xenopus laevis; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: C586834:6-chloro-4-ethyl-3,4-dihydro-2H-thieno(2,3-e)-1,2,4-thiadiazine 1,1-dioxide; D001581:Benzothiadiazines; D003499:Cyclic S-Oxides; D018690:Excitatory Amino Acid Agonists; D018091:Receptors, AMPA; D013829:Thiadiazines; D013876:Thiophenes; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D003981:Diazoxide; D009638:Norepinephrine